A special CRC subtype characterized by a high tumor mutational burden (TMB), more tumor neoantigens, and a higher density of tumor infiltrating lymphocytes.
Mismatch repair deficiency (dMMR) is found in up to 15% of non metastatic colon cancers.
dMMR results in micro satellite instability – high status, which is characterized by hypermutation immune checkpoint up regulation and abundant predicted neoantigens
The likelihood of MSI status in CRC varies according to the stage of disease: approximately 20% in stage I-II, 12% in stage III , and 4 to 5% in stage IV.
About 1/3 of MSI CRC arises from underlying variant DNA mismatched repair genes – MLH1 MSH2, MSH6, PMS2, EPCAM.
Pathogenic germ line variants in the DNA mismatch repair genes are the hallmark of the Lynch syndrome, which has almost universal MSI status of associated cancers.
Most MSI CRC (80–90%) are sporadic and arise from MLH1 hypermethylation, associated with high CpG methylation phenotype.
Defects in the DNA mismatch repair machinery can be identified by detecting the loss of MMR protein expression by the use of immunohistochemical analysis, or by detection of microsatellite instability with the use of PCR essays.
These immunogenic features make dMMR CRC highly responsive to treatment with PD-1 blockade.
dMMR CRC is not benefited by neoadjuvant chemotherapy.
Fluoropyramidines are intrinsically resistant to colorectal cancer with MMR, but not to combinations of fluorodines plus oxaliplatinum.
PD-1 blockade of dMMR CRC is highly effective with objective response rates in all patients, and 60% achieving pathologic complete response.
100% of patients with localized dMMR rectal cancer achieves a complete remission after six months of treatment PD-1 blockade.
Results of neoadjuvant immunotherapy for localized dMMR CRC show high rates of major and complete pathological response (Emilojou O).
In patients with locally advanced dMMR colon cancer, neoadjuvant nivolumab plus ipilimumab had an acceptable profile and lead to pathological response in a high proportion of patients (Chalabi, M).
Progression free survival is longer with nivolumab plus ipilimumab than with chemotherapy among patients who had not previously received systemic treatment for MSI-H or dMMR metastatic colon cancer.
The addition of atezolizumab to mFOLFOX6a significantly improves disease free survival among patients with stage III dMMR colon cancer (ATOMICTrial).
The use of immune checkpoint inhibitors in deficient mismatch repair/micro satellite unstable – high metastatic colon cancer faces two substantial challenges: primary resistance, progressive disease at first disease assessment, usually two months is observed in 15 to 30% of these patients.
The second challenge is determine when to discontinue treatment in patients with disease control as there are long-term toxic effects and significant healthcare costs: early ctDNA monitoring assists in management.